1. Field of the Invention
The invention relates to the field of novel therapies aimed to eliminate, kill or inhibit undesired body fluid species, such as pathogen microbes responsible for human and animal infections. More particularly the invention relates to an enhanced photodynamic therapy capable of eliminating or destroying undesired body fluid species, such as bacteria, in complex environment like whole blood, blood serum and other human and animal body fluids.
2. Invention Disclosure Statement
Photodynamic therapy (PDT) has emerged as a promising treatment of cancer and other diseases utilizing activation of an external chemical agent called photosensitizer or PDT drug, by light. Photosensitizers are administered systemically, locally or topically. After a determined period of time after being administered, the photosensitizer is preferentially retained by the tissue to be treated as compared to its concentration on healthy cells. Subsequently light of specific wavelength is delivered to the site to be treated. The PDT drug absorbs the light, rises to an excited state and then reacts with local oxygen producing reactive oxygen species that can destroy the cells which have retained a high concentration of photosensitizer, with minimal damage to surrounding healthy cells. Moreover, PDT has the advantage of dual selectivity, in that a photosensitizer can be targeted to its destination cell or tissue and, in addition, the illumination can be spatially directed to the lesion destination too.
While PDT has been shown to be an effective therapy regarding its selectivity and efficiency to treat cancer cells it has also been shown to be useful in treating infectious diseases caused by many but not all pathogen bacteria. Moreover, with the recent number of reports about bacterial strains becoming resistant to frequent doses of antibiotics, PDT appears to be an attractive alternative to conventional antibacterial methods.
Regardless of its potential as a promising therapy, there are still some issues to be solved concerning its antimicrobial effectiveness in different body fluids. Antibacterial PDT has been demonstrated to work well in aqueous environments, while in blood serum its effectiveness is diminished. Moreover, it has been found that bacterial cells in complex media (e.g. whole blood, plasma, blood serum) are much less susceptible to standard photosensitizers due to the blocking action of the components of the blood, such as albumin, whose presence decreases the activity of photosensitizers. It is speculated that albumin present in blood serum competes with bacteria by its adhesion to typical photosensitizers and captures a disproportionate amount at higher serum concentrations rendering typical PDT treatments ineffective. Whereas some photosensitizers can provide sufficient killing rates at half blood serum concentration, efforts to kill bacteria effectively in an environment saturated with blood serum are usually frustrated. In consequence, a method capable of dealing with the competition effect between blood serum components and typical photosensitizer compounds would be advantageous in order to enhance PDT treatments.
Additionally, none of the known photosensitizers and their conjugates is effective against all bacteria, as activity remains somewhat dependent on the chemical structure of the photosensitizers. Furthermore, Gram (−) bacterial cells have generally been the hardest to inactivate due to their protective double-layer outer membrane, making them resistant to many antimicrobial therapies.
In an attempt to effectively destroy bacteria, including Gram (+) and (−) bacteria, in complex media, such as blood serum, Patent Publications WO/2005/021094 and US 2005/0049228 disclose a method and composition utilizing Safranin O, a red dye that absorbs in the 450-600 nm, and electromagnetic radiation. While it successfully addresses a very good killing in the case of Gram (+) bacteria and sufficient killing of some Gram (−) bacteria in complex media, it would be desirable to obtain a more efficient destroying and killing effect in complex media than available in the prior art.
Once again, aiming to have a broad-spectrum antimicrobial activity in PDT therapy, Patent Application WO2006/093891A2 discloses a method for providing antimicrobial therapy and photosensitizer compounds for PDT, based on functionalized fullerene molecules. The method includes directing light onto the administered fullerene species to produce cytotoxic species and kill microbial cells. Even though the invention copes with killing both Gram (−) and Gram (+) bacteria, it has proved to be effective only in PBS and serum, and there is no mention about fullerene photosensitizer compound effectiveness in an environment saturated with blood serum, human plasma or human blood. These complex body fluids have proteins that are more likely to bind the photosensitizer, thus diminishing the actual concentration available to bind to bacteria.
Thus, there is a need to enhance the effectiveness of prior art antimicrobial PDT treatments, aiming to kill, destroy or inactivate a wide variety of microbes causing infectious diseases, including the more resistant Gram (−) bacterial cells, in saturated blood serum, whole blood and other complex body fluids, commonly present in real patient treatment settings.